SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells
- The Institute of Cancer Research, London, United Kingdom
- CIC bioGUNE, Spain
Abstract
SOX11 is an embryonic mammary epithelial marker that is normally silenced prior to birth. High SOX11 levels in breast tumours are significantly associated with distant metastasis and poor outcome in breast cancer patients. Here, we show that SOX11 confers distinct features to ER-negative DCIS.com breast cancer cells, leading to populations enriched with highly plastic hybrid epithelial/mesenchymal cells, which display invasive features and alterations in metastatic tropism when xenografted into mice. We found that SOX11+DCIS tumour cells metastasize to brain and bone at greater frequency and to lungs at lower frequency compared to cells with lower SOX11 levels. High levels of SOX11 leads to the expression of markers associated with mesenchymal state and embryonic cellular phenotypes. Our results suggest that SOX11 may be a potential biomarker for breast tumours with elevated risk of developing metastases and may require more aggressive therapies.
Data availability
Sequencing data have been deposited in ArrayExpress as accession E-MTAB-9108. All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Breast Cancer Now (Programme Funding to the Breast Cancer Now Toby Robins Research Centre)
- Erik Oliemuller
- Richard Newman
- Siu Man Tsang
- Gareth Muirhead
- Farzana Noor
- Syed Haider
- Beatrice A Howard
Cancer Research UK (CRUK: A21855)
- Shane Foo
Spanish Ministry of Education and Science (SAF2017-84934-R)
- Maria dM Vivanco
Government of the Autonomous Community of the Basque Country, the Department of Industry, Tourism and Trade
- Iskander Aurrekoetxea-Rodríguez
- Maria dM Vivanco
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal work was carried out under UK Home Office PPL number: PB0FA698C (BAH Project licence holder) and personal licenses following local ethical approval of all protocols from The Institute of Cancer Research Ethics Committee and in accordance with local and national guidelines. All surgery was performed under isoflurane anesthesia with appropriate analgesia, and every effort was made to minimise suffering.
Copyright
© 2020, Oliemuller et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,269
- views
-
- 288
- downloads
-
- 31
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells
eLife 9:e58374.
https://doi.org/10.7554/eLife.58374
Further reading
-
- Cancer Biology
- Chromosomes and Gene Expression
Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high-throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD in human cells. This screen implicated disruption of kinase SMG1’s phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from human and murine truncating mutations in vitro and murine cells in vivo. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable human leukocyte antigens (HLA) class I-associated peptides from NMD-downregulated proteins on the surface of human cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.
-
- Cancer Biology
For traditional laboratory microscopy observation, the multi-dimensional, real-time, in situ observation of three-dimensional (3D) tumor spheroids has always been the pain point in cell spheroid observation. In this study, we designed a side-view observation petri dish/device that reflects light, enabling in situ observation of the 3D morphology of cell spheroids using conventional inverted laboratory microscopes. We used a 3D-printed handle and frame to support a first-surface mirror, positioning the device within a cell culture petri dish to image cell spheroid samples. The imaging conditions, such as the distance between the mirror and the 3D spheroids, the light source, and the impact of the culture medium, were systematically studied to validate the in situ side-view observation. The results proved that placing the surface mirror adjacent to the spheroids enables non-destructive in situ real-time tracking of tumor spheroid formation, migration, and fusion dynamics. The correlation between spheroid thickness and dark core appearance under light microscopy and the therapeutic effects of chemotherapy doxorubicin and natural killer cells on spheroids’ 3D structure was investigated.
